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In general, severe bleeding disorders are uncommon, unlike mild bleeding problems, which can be more challenging to diagnose. Most episodes of clinically significant bleeding requiring medical attention result from local causes (eg, a duodenal ulcer), surgery, or trauma. However, it is important to recognize when bleeding problems are more serious or more frequent due to an underlying hemostatic abnormality.

Abnormal bleeding represents an important health care problem. For example, in the United States, it has been estimated that at least 5% to 10% of women of childbearing age seek medical care for menorrhagia and have bleeding severe enough to require medical intervention. Among the many defects that can cause abnormal bleeding, inherited and acquired von Willebrand disease (VWD) and platelet function disorders are much more common than defects in coagulation and fibrinolytic proteins.

PATHOPHYSIOLOGY

REVIEW OF NORMAL HEMOSTASIS

Hemostasis consists of the following steps: (1) initiation and formation of the platelet plug, also known as primary hemostasis; (2) propagation and amplification of the clotting “cascade” or secondary hemostasis, which involves activation of a series of coagulation factors resulting in the generation of thrombin that cleaves fibrinogen to fibrin; (3) cross-linking of fibrin; (4) termination of procoagulant response by antithrombotic control mechanisms; (5) removal of the clot by fibrinolysis; and (6) tissue repair and regeneration.

When a vessel is injured, platelets adhere to exposed collagen and other components of the subendothelium as the first defense against bleeding. This initial adhesion is dependent on von ­Willebrand factor (VWF) as well as specific platelet receptors (eg, glycoprotein IbIXV) for VWF and collagen. This adhesion leads to platelet activation and shape change as well as platelet aggregation, which promotes recruitment of additional platelets.

Coagulation is initiated in vivo when endothelial or vascular cells are damaged. This results in exposure of blood to tissue factor (TF), which binds to factor VII (FVII) and its activated form, factor VII (FVIIa). TF-FVIIa complexes (extrinsic tenase) then activates factors IX and X directly. Activated factor IX can also form a complex with factor VIIIa as well as phospholipids and calcium, called the intrinsic tenase complex, which promotes further conversion of factor X to factor Xa. The generated factor Xa associates with activated factor V, phospholipids, and calcium to form the prothrombinase complex that activates prothrombin to thrombin. Intrinsic and extrinsic tenase are needed to generate enough thrombin for normal hemostasis. Once thrombin is generated, it cleaves fibrinogen to fibrin, which leads to formation of a fibrin clot and promotes platelet activation and the generation of activated factors V and VIII. Thrombin also results in ...